Abstract
AimsAspirin has been used for the secondary prevention and treatment of cardiovascular disease for several decades. We investigated the roles of transcriptional factor activator protein 2α (AP-2α) in the beneficial effects of aspirin in the growth and vulnerability of atherosclerotic plaque.Methods and ResultsIn mice deficient of apolipoprotein E (Apoe-/-), aspirin (20, 50 mg/kg/day) suppressed the progression of atherosclerosis in aortic roots and increased the plaque stability in carotid atherosclerotic plaques induced by collar-placement. In vivo lentivirus-mediated RNA interference of AP-2α reversed the inhibitory effects of aspirin on atherosclerosis in Apoe-/- mice. Mechanically, aspirin increased AP-2α phosphorylation and its activity, upregulated IkBα mRNA and protein levels, and reduced oxidative stress in cultured vascular smooth muscle cells. Furthermore, deficiency of AP-2α completely abolished aspirin-induced upregulation of IkBα levels and inhibition of oxidative stress in Apoe-/- mice. Clinically, conventional doses of aspirin increased AP-2α phosphorylation and IkBα protein expression in humans subjects.ConclusionAspirin activates AP-2α to upregulate IkBα gene expression, resulting in attenuations of plaque development and instability in atherosclerosis.
Highlights
Atherosclerosis, formerly considered a bland lipid storage disease, involves an ongoing inflammatory response [1]
Aspirin suppressed the growth of atherosclerosis lesion and promoted the plaque stability. All these effects of aspirin were abolished by knockdown of activator protein 2α (AP-2α) via genetic approaches
An important finding of this study is that aspirin via AP-2α activation inhibits the growth and instability atherosclerotic plaques
Summary
Atherosclerosis, formerly considered a bland lipid storage disease, involves an ongoing inflammatory response [1]. In the early stage of atherosclerosis, the abnormal homeostatic functions of the endothelium appear and promote an inflammatory response. Later in the process, increased inflammation stimulates enlargement of the plaque lesion weakening the protective fibrous cap of the atheroma [2], possibly leading to thrombosis and the occurrence of acute coronary syndrome. Mice deficient in AP-2 die after birth due to the abnormal skeletal and neural tube development, indicating a critical role of AP-2 in mammals [4, 5]. AP-2α recognizes the consensus DNA sequence of 5′-GCCNNNGGC-3′ found in a number of genes involved in various cell functions [6]. The biological role and clinical relevance of AP-2α in atherosclerosis have not been elucidated
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